Brain metastasis in a patient with BRCA2-mutated treatment-related neuroendocrine prostate carcinoma and long-term response to radiotherapy and Olaparib: A case report and literature review

Background: A new subtype of prostate cancer called treatment-related neuroendocrine prostate carcinoma (t-NEPC) was added to the revised World Health Organization classification of prostate cancer in 2022. t-NEPC cases are increasing, and there is no established standard treatment. Methods: A 49-year-old male patient was referred to our department for dysuria. A rectal examination and a prostate biopsy revealed stony hardness and prostate adenocarcinoma, respectively. Imaging studies confirmed the presence of multiple bone and lymph node metastases. The patient was started on upfront treatment with androgen deprivation therapy and an androgen receptor signaling inhibitor, which resulted in a significant (>90%) decrease in prostate-specific antigen (PSA) levels. The patient experienced postrenal failure 6 months later, attributable to local disease progression. Concurrently, there was an elevation in neuron-specific enolase (NSE) levels and an enlargement of pelvic lymph node metastases, without PSA progression. Results: Biopsy specimen for cancer genome profiling revealed deletion of BRCA 2 and PTEN, AR amplification, and the presence of the TMPRSS2-ERG fusion gene. Based on increased NSE and BRCA2 mutations, a diagnosis of t-NEPC with BRCA2 mutation was eventually made. The patient received docetaxel chemotherapy and pelvic radiotherapy. Subsequently, he was treated with olaparib. His NSE levels decreased, and he achieved a complete response (CR). However, 18 months following the olaparib administration, brain metastases appeared despite the absence of pelvic tumor relapse, and the patient’s PSA levels remained low. Consequently, the patient underwent resection of the brain metastases using gamma knife and whole-brain radiotherapy but died approximately 3 months later. Conclusion subsections: Platinum-based chemotherapy is often administered for the treatment of t-NEPC, but there are few reports on the effectiveness of olaparib in patients with BRCA2 mutations. In a literature review, this case demonstrated the longest duration of effectiveness with olaparib alone without platinum-based chemotherapy. Additionally, the occurrence of relatively rare, fatal brain metastases in prostate cancer after a long period of CR suggests the necessity of regular brain imaging examinations.


Introduction
Despite recent progress in treating castration-resistant prostate cancer (CRPC), some patients still have poor prognoses.One reason for changing cancer cells is their phenotypes, including transitioning to neuroendocrine prostate cancer (NEPC).Recently, a new subtype of prostate cancer called treatment-related NEPC (t-NEPC) was added to the revised World Health Organization classification of prostate cancer. [1]On the other hand, CRPC with BRCA mutations has been the focus of much research due to its unique genetic makeup and challenging prognosis. [2]A recent study showed that olaparib, a polyadenosine diphosphate-ribose polymerase (PARP) inhibitor, is a promising treatment option for CRPC with BRCA mutations, surpassing the efficacy of androgen receptor-signaling inhibitors. [2]These have opened up new treatment avenues for various malignancies; however, patients with t-NEPC and BRCA mutations are rare and the standard treatment is not established.In this report, we describe a unique case of t-NEPC with a BRCA2 mutation, highlighting the sustained effectiveness of olaparib treatment.Additionally, we conducted a review of literature on similar cases of t-NEPC with BRCA2 mutation treated with olaparib.This review aims to clarify the clinical features associated with BRCA2 mutations in t-NEPC and to explore potential treatment strategies.

Case report
A 49-year-old male was presented to our hospital with a 6-month history of frequent urination.He had a family history of prostate cancer; his father had suffered from this condition.A rectal examination indicated a stony hardness.Blood tests revealed elevated alkaline phosphatase (489 U/L) and prostate-specific antigen (PSA) levels (162.3 ng/mL).Following a prostate biopsy, the patient was diagnosed with adenocarcinoma, with a Gleason score of 4 + 5 = 9 (Fig. 1A).Further imaging through computed tomography revealed multiple lymph node metastases and bone scintigraphy identified multiple bone metastases (Fig. 1B, C).Based on these findings, the patient was diagnosed with high-risk metastatic prostate cancer.Treatment with antiandrogen deprivation therapy and apalutamide was promptly commenced.However, 6 months later, the patient developed postrenal failure due to local progression and enlarged pelvic lymph node metastasis, yet without PSA progression (Fig. 2).Subsequently, after bilateral nephrostomy, docetaxel chemotherapy was administered, which resulted in an elevated level of neuron-specific enolase (NSE) (Fig. 2).Therefore, we added pelvic radiotherapy and submitted initial prostate biopsy specimens for cancer genome profiling.The cancer genome profiling revealed deletion of BRCA 2 and PTEN, AR amplification, and the presence of the TMPRSS2-ERG fusion gene.After switching the treatment from docetaxel to olaparib, NSE levels decreased, and the patient achieved a complete response (CR) (Fig. 2).However, 18 months following the olaparib administration, brain metastases appeared despite the absence of pelvic tumor relapse, and the patient's PSA levels remained low (Fig. 2).Subsequently, resection of the brain metastases using a gamma knife and whole-brain radiotherapy were performed.Pathological findings revealed metastatic cancer with positive neuroendocrine tumor markers and negative PSA, which differed significantly from the prostate biopsy specimen (Fig. 3).The patient died approximately 3 months after radiation therapy.

Discussion and literature review
Herein, we present a rare case of t-NEPC with a BRCA2 mutation that showed the long-term efficacy of olaparib.There are 2 primary forms of drug resistance in cancer treatment: primary resistance and acquired resistance. [3]Primary resistance refers to the inherent resistance present at the onset of treatment.This arises when the treatment fails to effectively target the factors causing cancer, leading to an inability to suppress signals that promote cancer growth.Conversely, acquired resistance develops subsequent to initial treatment, either due to the expansion of preexisting resistant clones under therapeutic pressure or through the adaptation of cells that develop resistance mechanisms during treatment.Acquired resistance emerges over time and is a consequence of alterations in cancer cells posttreatment.In this context, AR amplification and BRCA2 mutations exemplify primary resistance, while t-NEPC is indicative of acquired resistance. [3]Recent discoveries regarding prostate cancer have uncovered its capacity to transform into NEPC as a result of therapy, which is referred to as lineage plasticity. [4,5]This case is significant because, although AR amplification in primary prostate cancer tissues is usually linked to resistance to ARSI. [6]RSI proved effective in treating tumors that produced PSA in this instance.Nevertheless, the patient underwent a recurrence in a relatively brief span, exhibiting a PSA-negative and NSEpositive profile.Metastatic cancer sites are known to possess a variety of genetic mutations, each exhibiting heterogeneity. [7,8]his heterogeneity may be related to the reason why, despite the initial effectiveness of ARSI, the patient experienced a relatively quick recurrence and presented a different tumor marker profile.
In a previous case report, [9] chemotherapy was a viable treatment option for NEPC.However, in this particular case, we highlight the long-term effectiveness of PARP inhibitors.[12][13][14][15][16][17][18][19][20][21][22] Of these, 5 cases from 4 articles involved individuals who had no prior history of cancer and were administered olaparib (Table 1). [12,15,21,22]In terms of age and initial PSA levels, the patient was younger and had a significantly higher PSA value than did the other cases presented in the Table 1.Furthermore, specific mutations such as PTEN, AR amplification, and TMPRSS2-ERG fusion were observed in prostate cancer specimens.Unlike other cases in which all patients underwent platinum-based chemotherapy, this case did not involve such treatment but instead utilized radiation therapy.Notably, the longest duration of CR was achieved with olaparib.Additionally, the recurrence of brain metastasis in this case is a distinctive feature compared with the other cases presented.
The distinct features observed in the present case may be linked to the BRCA2 mutations and radiation therapy.Recent studies on patient-derived xenografts of neuroendocrine prostate cancer with BRCA mutations have reported substantial tumor-suppressive effects by PARP inhibitors. [23]This suggests a possible connection between BRCA mutations and t-NEPC as driver mutations.In addition, prior research has also indicated that olaparib may exhibit radiosensitizing effects, particularly for lung cancer. [24]onsistent with the previous report, [9] we noted the presence of multiple metastatic lesions in the brain without local recurrences.Our findings underscore the challenges associated with achieving sufficient drug penetration across this barrier.Based on the previous report [9] and our patient, recurrence of brain metastasis is a common occurrence with t-NEPC, underscoring the need for regular brain imaging examinations and not solely abdominal imaging.

Conclusion
The incidence of t-NEPC is on the rise, yet there is no established treatment protocol.Nonetheless, there is some indication that PARP inhibitors may be beneficial in cases where BRCA anomalies are present.We suggest that patients receiving olaparib for CRPC with BRCA mutations undergo regular brain imaging.Table 1 List of cases used in the literature review for neuroendocrine prostate cancer with BRCA2 mutation and olaparib treatment.

Figure 3 .
Figure 3. Pathological characteristics of prostate biopsy specimens and metastatic brain specimens.PSA and neuroendocrine tumor markers corresponding to the same locations as the HE staining are presented.HE = hematoxylin and eosin, PSA = prostate-specific antigen.